Surfactant protein D (SP-D) is a member of the collectin family of proteins. In the lung, SP-D binds bacterial, viral, and fungal pathogens and facilitates the clearance of these organisms. SP-D also binds inflammatory molecules, such as lipopolysaccharide, and limits the inflammatory damage that these molecules induce. As a consequence of its role in the lung immune system, SP-D is being developed as a therapeutic agent designed to limit the growth of microorganisms in the lung and the resulting inflammatory damage. SP-D is also produced in many non-pulmonary locations;however, the source and functions of extrapulmonary SP-D are unknown. Our preliminary results suggest that SP-D is also involved in systemic host defense. Therefore, this application seeks to test the general hypothesis that SP-D plays a role in the clearance of systemic pathogens and regulates systemic host defense. To test this hypothesis we will determine if intravenously injected SP-D improves inflammation, tissue damage and survival in mice exposed to lipopolysaccharide or live bacterial challenge. We will determine the site(s) of production and clearance of systemic SP-D and the transcriptional mechanisms that control production of systemic SP-D. We will identify the structural features of SP-D required for regulating systemic host defense cells. These studies will advance our understanding of the role of SP-D in systemic host defense. In addition, these studies will form the foundation for future translational studies to test SP-D in treatment of systemic infection and septic shock. The principle investigator of this grant has completed a Ph.D. in biochemistry, a clinical fellowship in neonatology, and is currently an Assistant Professor in the Section of Neonatology, Perinatal and Pulmonary Biology. Throughout his training, he has demonstrated repeated commitment to a career in scientific research. The experiments and training outlined in this grant will significantly broaden the skills and knowledge of the principle investigator and facilitate his development into an independent clinical scientist.